Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
  • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5015—Organic compounds, e.g. fats, sugars
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to modified release formulations of gamma-hydroxybutyrate having improved pharmacokinetic (PK) properties, and to therapeutic uses thereof.
• PK pharmacokinetic
• Narcolepsy is a devastating disabling condition.
• the cardinal symptoms are excessive daytime sleepiness (EDS), cataplexy (a sudden loss of muscle tone triggered by strong emotions, seen in approximately 60% of patients), hypnogogic hallucination (HH), sleep paralysis (SP), and disturbed nocturnal sleep (DNS).
• EDS daytime sleepiness
• HH hypnogogic hallucination
• SP sleep paralysis
• DNS disturbed nocturnal sleep
• DNS is the most common symptom seen among narcolepsy patients.
• narcolepsy rests in part on clinical grounds.
• PSG polysomnogram
• MSLT multiple sleep latency test
• REM rapid eye movement
• a mean sleep latency less than or equal to 8 minutes and two or more sleep onset REM periods (SOREMPs) are required to confirm a diagnosis of Type 1 or Type 2 narcolepsy.
• SOREMPs sleep onset REM periods
• narcolepsy be diagnosed by measuring hypocretin in the cerebrospinal fluid (CSF) in cases where the PSG and/ or MSLT is not completed. For these cases, a hypocretin concentration of less than 110 pg/nL confirms a narcolepsy Type 1 diagnosis.
• narcolepsy One of the major treatments for narcolepsy is sodium oxybate, a neuroactive agent with a variety of Central Nervous System (CNS) pharmacological properties.
• the species is present endogenously in many tissues, where it acts as a neurotransmitter on a gamma-hydroxybutyrate (GHB) receptor (GHBR), and possesses neuromodulatory properties with significant effects on dopamine and gamma-Aminobutyric Acid (GABA).
• GABA gamma-Aminobutyric Acid
• Studies have suggested that sodium oxybate improves Rapid Eye Movement Sleep (REM sleep, REMS) of narcoleptics in contrast to antidepressant drugs.
• REM sleep Rapid Eye Movement Sleep
• REMS Rapid Eye Movement Sleep
• Sodium oxybate is also known as sodium 4-hydroxybutanoate, or gamma-hydroxybutyric acid sodium salt, and has the following chemical structure:
• Sodium oxybate is marketed commercially in the United States as Xyrem ® .
• the product is formulated as an immediate release liquid solution that is taken once immediately before bed, and a second time approximately 2.5 to 4 hours later, in equal doses. Sleep-onset can be dramatic and fast, and patients are advised to be sitting in bed when consuming the dose. The most commonly reported side effects are confusion, depressive syndrome, incontinence and sleepwalking.
• the recommended starting dose is 4.5 g divided into 2 equal doses of 2.25 g, the first taken at bedtime and the second taken 2.5 to 4 hours later.
• the starting dosage can be decreased to 3.0 g/day or increased to as high as 9.0 g/day in increments of 1.5 g/day (0.75 g per dose).
• Two weeks are recommended between dosage adjustments to optimize reduction of daytime symptoms and minimize side effects.
• the ideal dose will provide an effective eight hours of sleep but, at the end of eight hours, very little of the drug will remain in the patient's bloodstream to affect the patient's wakefulness.
• Allphin for example, conducted two separate crossover bioavailability trials involving three separate modified release formulations and an immediate release solution, and reported the following bioavailability results: Summary of PK Parameters for Treatments A, B, C ⁇ _z (1/hr) T 1/2 (hr) Tmax (hr) a Cmax (ug/ml) AUClast (hr * ug/ml) AUCinf (hr * ug/ml) Treatment A N 29 29 29 29 29 29 29 Mean 1.22 0.6 4.50 (0.5, 4.75) 130.79 350.84 351.2 SD 0.27 0.13 31.52 116.74 116.74 CV % 21.93 22.61 24.1 33.27 33.24 Mean 1.19 0.58 127.3 333.33 333.72- Treatment B N 18 18 19 19 19 19 18 Mean 0.62 1.22 2.00 (1.50, 5.00) 41.78 188.23 196.25 SD 0.16 0.40 18.40 103.60 102.50 CV % 26.44 32.58 44
• Mean AUC inf for Treatment D was only 22% of the mean AUC inf of Treatment A, although Treatment D dosed 2 g less of sodium oxybate than Treatment A, which, compared to same dose, represented only 33% of the mean AUC inf of Treatment A.
• Allphin's formulations also suffered from an excess of sodium oxybate remaining in the bloodstream at 8 hours.
• Liang Liang et al.
• Legrand provides a system ensuring that the active ingredient is released with certainty from the modified release dosage form by means of a dual mechanism of "time-dependent” and "pH-dependent” release. Legrand did not describe any dosage forms for delivering sodium oxybate or other forms of gamma-hydroxybutyrate.
• Xyrem ® Another drawback of Xyrem ® is the high level of the daily dose, generally 7.5g or 9g of sodium oxybate taken daily over long periods of time. This represents a very high sodium intake which is not recommended in persons with high blood pressure, risk of cardiovascular disease, stroke or coronary heart disease (See WHO. Guideline: Sodium intake for adults and children. Geneva, World Health Organization (WHO), 2012 .).
• one object of the present invention is to provide modified release formulations of gamma-hydroxybutyrate that are administered only once at bed-time with improved dissolution and pharmacokinetic profiles.
• Another object of the present invention is to provide modified release formulations of gamma-hydroxybutyrate that optimize the bioavailability of the gamma-hydroxybutyrate, and roughly approximate the bioavailability of an equal dose of an immediate release liquid solution of sodium oxybate administered twice nightly.
• Still another object of the present invention is to provide once-nightly modified release formulations of gamma-hydroxybutyrate that roughly approximate or exceed the bioavailability of an equal dose of an immediate release solution of sodium oxybate administered twice nightly, across the entire therapeutic range of sodium oxybate doses.
• Yet another object of the present invention is to provide modified release formulations of gamma-hydroxybutyrate which, 8 hours after administration, produce very little residual drug content in the bloodstream of most patients but still similar to the one observed after administration of an equal dose of an immediate release liquid solution of sodium oxybate administered twice nightly.
• Yet another object of the present invention is to improve the therapeutic effectiveness and safety profile of gamma-hydroxybutyrate based on novel dissolution and pharmacokinetic profiles.
• Yet another object of the present invention is to provide modified release formulations of gamma-hydroxybutyrate that yield a similar pharmacokinetic profile compared to an immediate release liquid solution of sodium oxybate administered twice nightly while potentially giving a reduced dose.
• Yet another object of the present invention is to provide modified release formulations of gamma-hydroxybutyrate that allow once daily administration and reduced dose compared to the commercial treatment Xyrem ® .
• the inventors have discovered a novel relationship between the in vitro release profile of gamma-hydroxybutyrate modified release formulations and in vivo absorption which permits, for the first time, a modified release formulation of gamma-hydroxybutyrate that approximates the bioavailability of a twice-nightly equipotent immediate release liquid solution of sodium oxybate, and that does so across a range of therapeutic doses.
• the modified release formulations of gamma-hydroxybutyrate preferably have both immediate release and modified release portions.
• the release of gamma-hydroxybutyrate from the immediate release portion is practically uninhibited, and occurs almost immediately in 0.1N hydrochloric acid dissolution medium.
• the modified release portion also preferably releases its gamma-hydroxybutyrate almost immediately when fully triggered, the release is not triggered until a predetermined lag-time or the drug is subjected to a suitable dissolution medium such as a phosphate buffer pH 6.8 dissolution medium.
• a suitable dissolution medium such as a phosphate buffer pH 6.8 dissolution medium.
• the invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, wherein a 7.5 g dose of the formulation has been shown to achieve a mean AUC inf of greater than 340 hr microgram/mL.
• the invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, wherein a 7.5 g dose of the formulation has been shown to achieve a mean AUC inf of greater than 340 hrxmicrogram/mL, and a mean C 8h that is from 50% to 130% of the mean C 8h provided by an equal dose of an immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses approximately two hours after a standardized evening meal.
• the invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, wherein the formulation releases (a) at least 80% of its gamma-hydroxybutyrate at 3 hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, and (b) from 10% to 65%, of its gamma-hydroxybutyrate at one hour and three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm.
• the invention provides a modified release formulation of gamma-hydroxybutyrate, comprising immediate release and modified release portions, wherein (a) the formulation releases at least 80% of its gamma-hydroxybutyrate at 3 hours, when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, (b) the formulation releases from 10% to 65%, of its gamma-hydroxybutyrate at one hour and three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, and (c) the modified release portion releases greater than 80% of its gamma-hydroxybutyrate at 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hours
• the invention provides a modified release formulation of gamma-hydroxybutyrate, comprising immediate release and modified release portions, wherein (a) the formulation releases at least 80% of its gamma-hydroxybutyrate at 3 hours, when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, (b) the formulation releases 10% to 65%, of its gamma-hydroxybutyrate at one hour and at three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, (c) the formulation releases greater than 60% of its gamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N
• the invention provides a modified release formulation of gamma-hydroxybutyrate, comprising immediate release and modified release portions, wherein (a) a 7.5 g dose of the formulation has been shown to achieve a mean AUC inf of greater than 340 hr microgram/mL, and a mean C 8h that is from 50% to 130%, of the mean C 8h provided by an equal dose of an immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses approximately two hours after a standardized evening meal, and (b) the formulation releases (i) at least 80% or 90% of its gamma-hydroxybutyrate at 3 hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, and (ii) from 10% to 65%, of its gamma-hydroxybutyrate at one hour
• the invention provides a modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, wherein: (a) said immediate release portion releases greater than 80% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm; (b) said modified release portion releases less than 20% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm; and (c) said modified release portion releases greater than 80% of its gamma-hydroxybutyrate at three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium
• the invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, that yields a dissolution profile substantially as depicted in Figure 20 and Figure 21 .
• a nineteenth principal embodiment of the present invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, that yields a plasma concentration versus time curve when administered once nightly at a strength of 4.5 g, 7.5 g or 9.0 g approximately two hours after a standardized evening meal substantially as depicted in Figure 90 for the corresponding strength.
• Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.
• ranges are given by specifying the lower end of a range separately from the upper end of the range, it will be understood that the range can be defined by selectively combining any one of the lower end variables with any one of the upper end variables that is mathematically and physically possible.
• a formulation may contain from 1 to 10 weight parts of a particular ingredient, or 2 to 8 parts of a particular ingredient, it will be understood that the formulation may also contain from 2 to 10 parts of the ingredient.
• a formulation may contain greater than 1 or 2 weight parts of an ingredient and up to 10 or 9 weight parts ofthe ingredient, it will be understood that the formulation may contain 1-10 weight parts of the ingredient, 2-9 weight parts of the ingredient, etc. unless otherwise specified, the boundaries of the range (lower and upper ends of the range) are included in the claimed range.
• the term “about” or “substantially” or “approximately” will compensate for variability allowed for in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in product strength due to manufacturing variation and time-induced product degradation.
• the term allows for any variation which in the practice of pharmaceuticals would allow the product being evaluated to be considered bioequivalent to the recited strength, as described in FDA's March 2003 Guidance for Industry on BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FOR ORALLY ADMINISTERED DRUG PRODUCTS - GENERAL CONSIDERATIONS.
• gamma-hydroxybutyrate refers to the free base of gamma hydroxy-butyrate, a pharmaceutically acceptable salt of gamma-hydroxybutyric acid, and combinations thereof, their hydrates, solvates, complexes or tautomers forms.
• “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
• formulation or “composition” refers to the quantitative and qualitative characteristics of a drug product or dosage form prepared in accordance with the current invention.
• the doses and strengths of gamma-hydroxybutyrate are expressed in equivalent-gram (g) weights of sodium oxybate unless stated expressly to the contrary.
• g equivalent-gram
• an embodiment is said to provide a 4.5g dose of gamma-hydroxybutyrate, because the form of gamma-hydroxybutyrate is not specified, it will be understood that the dose encompasses a 4.5g dose of sodium oxybate, a 5.1g dose of potassium gamma-hydroxybutyrate (assuming a 126.09 g/mol MW for sodium oxybate and a 142.20 g/mol MW for potassium gamma-hydroxybutyrate), and a 3.7g dose of the free base (assuming a 126.09 g/mol MW for sodium oxybate and a 104.1 g/mol MW for the free base of gamma-hydroxybutyrate), or by the weight of any mixture of salts of gamma-hydroxybutyric acid that provides the same amount of GHB as 4.5g of sodium oxybate.
• the terms "finished composition”, “finished formulation” or “formulation” are interchangeable and designate the modified release formulation of gamma-hydroxybutyrate preferably comprising modified release microparticles of gamma-hydroxybutyrate, immediate release microparticles of gamma-hydroxybutyrate, and any other excipients.
• an "immediate release (IR) portion" of a formulation includes physically discreet portions of a formulation, mechanistically discreet portions of a formulation, and pharmacokinetically discreet portions of a formulation that lend to or support a defined IR pharmacokinetic characteristic.
• any formulation that releases active ingredient at the rate and extent required of the immediate release portion of the formulations of the present invention includes an "immediate release portion," even if the immediate release portion is physically integrated in what might otherwise be considered an extended release formulation.
• the IR portion can be structurally discreet or structurally indiscreet from (i.e. integrated with) the MR portion.
• the IR portion and MR portion are provided as particles, and in an even more preferred subembodiment the IR portion and MR portion are provided as particles discreet from each other.
• coatings e.g., enteric coatings
• An ER product is formulated to make the drug available over an extended period after ingestion, thus allowing a reduction in dosing frequency compared to a drug presented as a conventional dosage form, e.g. a solution or an immediate release dosage form.
• extended-release is usually interchangeable with "sustained-release", “prolonged-release” or "controlled-release”.
• the dosage form, or the initial dosage form if the dosing regimen calls for more than one administration is administered approximately two hours after consumption of a standardized dinner consisting of 25.5% fat, 19.6% protein, and 54.9% carbohydrates.
• a first principal embodiment of the present invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, wherein a 7.5 g dose of the formulation has been shown to achieve a mean AUC inf of greater than 245, 300, 325, 340, 375, 400, 425, or 450 hrxmicrogram/mL, most preferably greater than 340 hrmicrogram/mL.
• a fourth principal embodiment of the present invention provides a modified release formulation of gamma-hydroxybutyrate, comprising immediate release and modified release portions, wherein (a) the formulation releases at least 80% or 90% of its gamma-hydroxybutyrate at 3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25 hours, preferably 1 hour, when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, (b) the formulation releases from 10 to 65%, from 15 to 60%, from 20 to 55%, from 25 to 55%, from 30 to 55%, from 35 to 55%, from 40 to 55%, from 40 to 60%, or from 45 to 55%, preferably from 40% to 60%, of its gamma-hydroxybutyrate at one hour and at three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1
• Xyrem ® administered at t 0 and t 4h in equally divided doses approximately two hours after a standardized evening meal, and (b) the formulation releases (i) at least 80% or 90% of its gamma-hydroxybutyrate at 3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25 hours, preferably 1 hour, when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, and (ii) from 10 to 65%, from 15 to 60%, from 20 to 55%, from 25 to 55%, from 30 to 55%, from 35 to 55%, from 40 to 55%, from 40 to 60%, or from 45 to 55%, preferably from 40% to 60%, of its gamma-hydroxybutyrate at one hour and three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of
• An eighth principal embodiment of the present invention provides a modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, wherein: (a) said immediate release portion releases greater than 80% or 90% of its gamma-hydroxybutyrate at one hour, two hours, or three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm; (b) said modified release portion releases less than 20% or 10% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm; (c) said modified release portion releases greater than 80% or 90% of its gamma-hydroxybutyrate at three hours, two hours, or one hour, when tested in a dissolution apparatus 2 according to USP 38
• a ninth principal embodiment of the present invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, wherein a 4.5g, 6g, 7.5g, and 9g dose of the formulation has been shown to achieve a relative bioavailability (RBA) of greater than 80%, 85% or 90% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses, when administered approximately two hours after a standardized evening meal.
• RBA relative bioavailability
• the relative bioavailability is even higher with larger doses, and with a 6.0 g or 7.5 g or 9.0 g dose is preferably greater than 90, 95 or 100% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses, when administered approximately two hours after a standardized evening meal.
• An eleventh principal embodiment of the present invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, that yields a plasma concentration versus time curve when administered once nightly at a strength of 4.5 g, 6.0 g, or 7.5 g approximately two hours after a standardized evening meal substantially as depicted in Figure 12 or Figure 13 for the corresponding strength.
• a twelfth principal embodiment of the present invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, that yields a plasma concentration versus time curve when administered once nightly at a strength of 4.5g approximately two hours after a standardized evening meal substantially as depicted in Figure 22 .
• the invention provides a modified release formulation of gamma-hydroxybutyrate, comprising immediate release and modified release portions that yields a dissolution profile between the minimum and maximum values depicted in Figure 27 and Figure 28 .
• the formulation preferably comprises immediate release and modified release portions, wherein the modified release portion comprises gamma hydroxybutyrate particles coated by a polymer carrying free carboxylic groups and a hydrophobic compound having a melting point equal or greater than 40°C, and the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35.
• the polymers comprising free carboxylic groups preferably have a pH dissolution trigger of from 5.5 to 6.97 and are preferably methacrylic acid copolymers having a pH dissolution trigger of from 5.5 to 6.97.
• the invention provides a modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, wherein: (a) the modified release portion comprises coated particles of gamma-hydroxybutyrate; (b) the coating comprises a polymer carrying free carboxylic groups and a hydrophobic compound having a melting point equal or greater than 40°C; and (c) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35.
• the invention provides a modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, a suspending or viscosifying agent, and an acidifying agent, wherein: (a) the modified release portion comprises coated particles of gamma-hydroxybutyrate; (b) the coating comprises a polymer carrying free carboxylic groups and a hydrophobic compound having a melting point equal or greater than 40°C; and (c) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35.
• the invention provides a modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, wherein: (a) the modified release portion comprises coated particles of gamma-hydroxybutyrate; (b) the coating comprises a polymer carrying free carboxylic groups and a hydrophobic compound having a melting point equal or greater than 40°C; (c) the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is from 0.4 to 4; (d) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and (e) the coating is from 10 to 50% of the weight of the particles.
• the invention provides a modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, wherein: (a) the modified release portion comprises coated particles of gamma-hydroxybutyrate; (b) the coating comprises a polymer carrying free carboxylic groups having a pH trigger of from 5.5 to 6.97 and a hydrophobic compound having a melting point equal or greater than 40°C; (c) the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is from 0.4 to 4; (d) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and (e) the coating is from 10 to 50% of the weight of the particles.
• each of the sub-embodiments can be used to further characterize and limit each of the foregoing principal embodiments.
• more than one of the following sub-embodiments can be combined and used to further characterize and limit each of the foregoing principal embodiments, in any manner that is mathematically and physically possible.
• a 7.5 g dose of the modified release formulation of gamma-hydroxybutyrate can be characterized as having been shown to achieve a mean C max of greater than 65, 70, 75, 80, 85, or 90 microgram/mL when administered once approximately two hours after a standardized evening meal.
• An upper limit on mean C max for such 7.5 g dose can be set at 125 or 100 microgram/mL.
• a 7.5g dose of the modified release formulation of gamma-hydroxybutyrate can be characterized as having been shown to achieve a mean C 8h that is from 50% to 130%, from 60% to 130%, from 70 to 130%, from 75% to 125%, from 80% to 125%, from 80 to 120%, or from 90% to 110% of the mean C 8h provided by an equal dose of immediate release liquid solution of gamma-hydroxybutyrate administered at t 0 and t 4h in two equally divided doses, when administered approximately two hours after a standardized evening meal.
• the entire modified release formulation of gamma-hydroxybutyrate releases greater than 30%, 35%, 40%, or 45%, and less than 70%, 65%, 60%, or 55%, of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm.
• the modified release portion releases greater than 80%, 85%, 90%, 95%, 98% or even 99% of its gamma-hydroxybutyrate at 3, 2, 1, 0.5 or 0.25 hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm.
• Still further embodiments can be defined based on the dissolution properties of the modified release portion of the modified release formulation of gamma-hydroxybutyrate in a 0.1N HCl dissolution medium.
• the modified release portion releases less than 20%, 15%, 10%, 5%, or even 2% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm.
• Further embodiments can be defined based on the dissolution properties of the immediate release portion of the modified release formulation of gamma-hydroxybutyrate in a 0.1N HCl dissolution medium.
• the immediate release portion releases greater than 80%, 85%, 90%, 95%, 98% or even 99% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm.
• the formulation releases (a) at least 80% of its gamma-hydroxybutyrate at three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, and (b) from 10% to 65%, of its gamma-hydroxybutyrate at one hour and three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm.
• the formulation comprises immediate release and modified release portions, and (a) the formulation releases at least 80% of its gamma-hydroxybutyrate at 3 hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, (b) the formulation releases 10% to 65% of its gamma-hydroxybutyrate at one hour and at three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, (c) the formulation releases greater than 60% of its gamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed
• the invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, wherein a 4.5g and 9g dose of the formulation has been shown to achieve a relative bioavailability (RBA) of greater than 80%, 85% or 90% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses, when administered approximately two hours after a standardized evening meal
• RBA relative bioavailability
• a 6.0g or 7.5g or 9.0g dose of the modified release formulation of gamma-hydroxybutyrate has been shown to achieve a relative bioavailability (RBA) of greater than 80%, 85%, 90%, 95% or 100% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses, when administered approximately two hours after a standardized evening meal.
• RBA relative bioavailability
• Additional embodiments can be defined by comparing a dose of the modified release formulation of gamma-hydroxybutyrate, administered once nightly, to the same dose of an immediate release liquid solution of sodium oxybate divided in half and administered twice nightly, 4 hours apart.
• a 4.5 g, 6.0 g, 7.5 g or 9.0 g dose of the modified release formulation of gamma-hydroxybutyrate has been shown to achieve a median T max within one hundred fifty, one hundred twenty, ninety, sixty or thirty minutes of the median T max of half the dose of an immediate release liquid solution of sodium oxybate, when administered approximately two hours after a standardized evening meal.
• a 4.5 g, 6.0 g, 7.5 g or 9.0 g dose of the modified release formulation of gamma-hydroxybutyrate has been shown to achieve a mean C 6h or mean C 7h greater than, and a mean C 10h less than, the mean C 4h of half the dose of an immediate release liquid solution of sodium oxybate, when administered approximately two hours after a standardized evening meal.
• Additional embodiments can be defined by comparing the pharmacokinetic profile of a dose of the modified release formulation of gamma-hydroxybutyrate administered once nightly to the same dose of an immediate release liquid solution of sodium oxybate divided in half and administered twice nightly, 4 hours apart.
• a modified release formulation of gamma-hydroxybutyrate according to the invention has been shown to achieve a ratio of its mean C 3h to the mean C max of the first half dose of the immediate release liquid solution of sodium oxybate from 0.6 to 1.2, preferably from 0.7 to 1.1 and most preferably from 0.8 to 1.
• a modified release formulation of gamma-hydroxybutyrate according to the invention has been shown to achieve a ratio of its mean C 4h to the mean C max of the first half dose of the immediate release liquid solution of sodium oxybate from 0.5 to 1.1, preferably from 0.6 to 1 and most preferably from 0.7 to 0.9.
• a modified release formulation of gamma-hydroxybutyrate according to the invention has been shown to achieve a ratio of its mean C 4.5h to the mean C max of the first half dose of the immediate release liquid solution of gamma-hydroxybutyrate from 0.5 to 1, preferably from 0.5 to 0.9 and most preferably from 0.6 to 0.8.
• a 7.5g dose of the modified release formulation of gamma-hydroxybutyrate has been shown to achieve a mean C 4h of 40 to 75 microgram/mL, preferably 45 to 69 microgram/mL and more preferably 51 to 64 microgram/mL.
• a 7.5g dose of the modified release formulation of gamma-hydroxybutyrate has been shown to achieve a mean C 4.5h of 35 to 67 microgram/mL, preferably 40 to 62 microgram/mL and more preferably 45 to 56 microgram/mL.
• a 7.5 g dose of the formulation has been shown to achieve a mean AUC inf of greater than 300 hr ⁇ microgram/mL and a mean C max of greater than 70 microgram/mL when administered once approximately two hours after a standardized evening meal.
• a 4.5, 6.0, 7.5 and 9.0 g dose of the formulation has been shown to achieve a mean AUC inf of greater than 80% of the mean AUC inf provided by an equal dose of immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses approximately two hours after a standardized evening meal, and a mean C 8h less than 95%, 90 or 85% of the mean C 8h provided by an equal dose of immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses approximately two hours after a standardized evening meal.
• Additional embodiments can be defined by comparing the pharmacokinetic profile of a dose of the modified release formulation of gamma-hydroxybutyrate administered once nightly to another dose of an immediate release liquid solution of sodium oxybate divided in half and administered twice nightly, 4 hours apart.
• a 7.5g dose of the modified release formulation of gamma-hydroxybutyrate has been shown to achieve a similar pharmacokinetic profile to the pharmacokinetic profile provided by a 2 x 4.5 g dose of sodium oxybate as an immediate release liquid solution administered for the first 4.5g two hours after a standardized evening meal and for the second 4.5g dose, 4 hours after the first dose.
• a modified release formulation of gamma-hydroxybutyrate according to the invention administered at the dose of 7.5g has been shown to achieve a ratio of its mean C 3h to the mean C max of the first 4.5g dose of the immediate release liquid solution of sodium oxybate from 0.5 to 1.1, preferably from 0.6 to 1 and most preferably from 0.7 to 0.9.
• a modified release formulation of gamma-hydroxybutyrate according to the invention has been shown to achieve a ratio of its mean C 4h to the mean C max of the first 4.5g dose of the immediate release liquid solution of sodium oxybate from 0.5 to 1, preferably from 0.6 to 0.9 and most preferably from 0.7 to 0.8.
• a modified release formulation of gamma-hydroxybutyrate according to the invention has been shown to achieve a ratio of its mean C 4.5h to the mean C max of the 4.5g dose of the immediate release liquid solution of sodium oxybate from 0.4 to 0.9, preferably from 0.5 to 0.8 and most preferably from 0.6 to 0.7.
• the modified release formulation of gamma-hydroxybutyrate comprises immediate release and modified release portions, wherein: (a) said immediate release portion releases greater than 80% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm; (b) said modified release portion releases less than 20% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm; and (c) said modified release portion releases greater than 80% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer
• the modified release formulation of gamma-hydroxybutyrate according to the invention achieves an in vitro dissolution profile:
• the modified release formulation of gamma-hydroxybutyrate according to the invention achieves an in vitro dissolution profile:
• the formulation achieves an in vitro dissolution profile: (a) measured in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, characterized by the percentage of gamma-hydroxybutyrate dissolved being: (i) from 40% to 65% at 1 hour, (ii) from 40% to 65% at 3 hours, (iii) greater than 45% at 8 hours, and (b) measured in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, characterized by the percentage of gamma-hydroxybutyrate dissolved being: (i) greater than 40% at 0.5 hour, and (ii) greater than 85% at 1 hour.
• the modified release formulations of gamma-hydroxybutyrate of the present invention can be provided in any dosage form that is suitable for oral administration, including tablets, capsules, liquids, orally dissolving tablets, and the like, but they are preferably provided as dry particulate formulations (i.e. granules, powders, coated particles, microparticles, pellets, microspheres, etc.), in a sachet or other suitable discreet packaging units.
• the formulation is in the form of a powder.
• a preferred particulate formulation will be mixed with tap water shortly before administration, preferably 50 mL.
• the formulation comprises immediate release and modified release portions, wherein: (a) the modified release portion comprises coated microparticles of gamma-hydroxybutyrate; and (b) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35.
• the formulation comprises immediate release and modified release portions, wherein: (a) the modified release portion comprises coated microparticles of gamma-hydroxybutyrate; and (b) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 40/60 to 60/40.
• the formulation comprises immediate release and modified release portions, wherein: (a) the modified release portion comprises coated microparticles of gamma-hydroxybutyrate; (b) the coating of said modified release particles of gamma-hydroxybutyrate comprises a polymer carrying free carboxylic groups and a hydrophobic compound having a melting point equal or greater than 40°C; (c) the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is from 0.4 to 4; (d) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35 or 40/60 to 60/40; and (e) the coating of said modified release particles of gamma-hydroxybutyrate is from 10 to 50% of the weight of the microparticles.
• the formulation comprises immediate release and modified release portions, wherein: (a) the modified release portion comprises coated particles of gamma-hydroxybutyrate; (b) the coating of said modified release particles of gamma-hydroxybutyrate comprises a polymer carrying free carboxylic groups having a pH trigger of from 5.5 to 6.97 and a hydrophobic compound having a melting point equal or greater than 40°C; (c) the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is from 0.4 to 4; (d) the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35 or 40/60 to 60/40; and (e) the coating said modified release particles of gamma-hydroxybutyrate is from 10 to 50% of the weight of the particles.
• the polymer carrying free carboxylic groups comprises from 100% poly (methacrylic acid, ethyl acrylate) 1:1 and 0% poly (methacrylic acid, methylmethacrylate) 1:2 to 2% poly (methacrylic acid, ethyl acrylate) 1:1 and 98% poly (methacrylic acid, methylmethacrylate) 1:2; and the hydrophobic compound comprises hydrogenated vegetable oil.
• the formulation includes excipients to improve the viscosity and the pourability of the mixture of the particulate formulation with tap water.
• the particulate formulation comprises, besides the immediate release and modified release particles of gamma-hydroxybutyrate, one or more suspending or viscosifying agents or lubricants.
• Medium viscosity sodium carboxymethyl cellulose corresponds to grade of sodium carboxymethyl cellulose whose viscosity, for a 2% solution in water at 25°C, is greater than 200 mPa ⁇ s and lower than 3100 mPa ⁇ s.
• Preferred suspending or viscosifying agents are xanthan gum, especially Xantural 75 TM from Kelco, hydroxyethylcellulose, especially Natrosol 250M TM from Ashland, Kappa carrageenan gum, especially Gelcarin PH812 TM from FMC Biopolymer, and lambda carrageenan gum, especially Viscarin PH209 TM from FMC Biopolymer.
• the modified release formulation of gamma-hydroxybutyrate comprises from 1 to 15% of viscosifying or suspending agents, preferably from 2 to 10%, more preferably from 2 to 5%, and most preferably from 2 to 3% of the formulation.
• the modified release formulation of gamma-hydroxybutyrate is in the form of a powder that is intended to be dispersed in water prior to administration and further comprises from 1 to 15% of a suspending or viscosifying agent selected from a mixture of xanthan gum, carrageenan gum and hydroxyethylcellulose or xanthan gum and carrageenan gum.
• Alternative packages of viscosifying or suspending agents include about 50mg xanthan gum (Xantural 75 TM ) and about 100mg carragenan gum (Gelcarin PH812 TM ), or about 50mg xanthan gum (Xantural 75 TM ), about 75mg hydroxyethylcellulose (Natrasol 250M TM ), and about 75mg carragenan gum (Viscarin PH109 TM ).
• the modified release formulation of gamma-hydroxybutyrate further comprises a lubricant or a glidant, besides the immediate release and modified release particles of gamma-hydroxybutyrate.
• Preferred lubricants and glidants are chosen from the group consisting of salts of stearic acid, in particular magnesium stearate, calcium stearate or zinc stearate, esters of stearic acid, in particular glyceryl monostearate or glyceryl palmitostearate, stearic acid, glycerol behenate, sodium stearyl fumarate, talc, and colloidal silicon dioxide.
• the preferred lubricant or glidant is magnesium stearate.
• the modified release formulation of gamma-hydroxybutyrate comprises about 0.5% of magnesium stearate.
• the modified release formulation of gamma-hydroxybutyrate is in the form of a powder that is intended to be dispersed in water prior to administration and further comprises: from 1.2 to 15% of an acidifying agent selected from malic acid and tartaric acid; and from 1 to 15% of a suspending or viscosifying agent selected from a mixture of xanthan gum, carrageenan gum and hydroxyethylcellulose or xanthan gum and carrageenan gum.
• the modified release formulation of gamma-hydroxybutyrate preferably includes an immediate release portion and a modified release portion of gamma-hydroxybutyrate, and in a particularly preferred embodiment, the formulation is a particulate formulation that includes a plurality of immediate release gamma-hydroxybutyrate particles and a plurality of modified release gamma-hydroxybutyrate particles.
• the molar percentage of gamma-hydroxybutyrate in the modified release portion relative to the total of gamma-hydroxybutyrate in the formulation preferably ranges from 90% to 35%, from 85 to 40%, from 80 to 45%, from 75 to 45%, from 70 to 45%, from 65 to 45%, from 60 to 45%, from 60 to 40%, or from 55 to 45%, preferably from 60% to 40%.
• the molar ratio of the gamma-hydroxybutyrate in the modified release portion relative to the total of gamma-hydroxybutyrate in the formulation is about 50%.
• the finished formulation comprises 50% of its sodium oxybate content in immediate-release particles consisting of 80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to 450 microns and 50% of its sodium oxybate content in modified release particles consisting of 10.5 % w/w of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns, layered with 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone TM K30 and finally coated with a coating composition consisting of 18% w/w of hydrogenated vegetable oil (Lubritab TM or equivalent), 4% of methacrylic acid copolymer type C (Eudragit TM L100-55 or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit TM S100 or equivalent).
• a coating composition
• the finished formulation comprises 50% of its sodium oxybate content in immediate-release particles consisting of 80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to 170 microns and 50% of its sodium oxybate content in modified release particles consisting of 10.5 % w/w of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 170 microns, layered with 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone TM K30 and finally coated with a coating composition consisting of 18% w/w of hydrogenated vegetable oil (Lubritab TM or equivalent), 4% of methacrylic acid copolymer type C (Eudragit TM L100-55 or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit TM S100 or equivalent).
• a coating composition
• the finished formulation comprises 50% of its sodium oxybate content in immediate-release particles consisting of 80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns and 50% of its sodium oxybate content in modified release particles consisting of 11.3% w/w of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns, layered with 60.5% w/w of sodium oxybate mixed with 3.2% w/w of Povidone TM K30 and finally coated with a coating composition consisting of 15 % w/w of hydrogenated vegetable oil (Lubritab TM or equivalent), 0.75% of methacrylic acid copolymer type C (Eudragit TM L100-55 or equivalent) and 9.25% of methacrylic acid copolymer type B (Eudragit TM S100 or equivalent
• the finished formulation comprises 50% of its sodium oxybate content in immediate-release particles consisting of 80.75% w/w of sodium oxybate, 4.25% w/w of Povidone TM K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 170 microns and 50% of its sodium oxybate content in modified release particles consisting of 11.3% w/w of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 170 microns, layered with 60.5% w/w of sodium oxybate mixed with 3.2% w/w of Povidone TM K30 and finally coated with a coating composition consisting of 15 % w/w of hydrogenated vegetable oil (Lubritab TM or equivalent), 0.75% of methacrylic acid copolymer type C (Eudragit TM L100-55 or equivalent) and 9.25% of methacrylic acid copolymer type B (Eudragit TM S100
• the finished formulation comprises 50% of its gamma-hydroxybutyrate content in immediate-release particles consisting of 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns and 50% of its gamma-hydroxybutyrate content in modified release particles consisting of 10.5 % w/w of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns, layered with 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone TM K30 and finally coated with a coating composition consisting of 18% w/w of hydrogenated vegetable oil (Lubritab TM or equivalent), 4% of methacrylic acid copolymer type C (Eudragit TM L100-55 or equivalent) and 8% of methacrylic acid copo
• the finished formulation comprises 16.7% ofits gamma-hydroxybutyrate content in immediate-release particles consisting of 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns, 16.7% of its gamma-hydroxybutyrate content in immediate-release particles consisting of 80.75% w/w of magnesium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns, 16.7% of its gamma-hydroxybutyrate content in immediate-release particles consisting of 80.75% w/w of calcium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume
• the finished formulation comprises 16.7% ofits gamma-hydroxybutyrate content in immediate-release particles consisting of 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 170 microns, 16.7% of its gamma-hydroxybutyrate content in immediate-release particles consisting of 80.75% w/w of magnesium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 170 microns, 16.7% of its gamma-hydroxybutyrate content in immediate-release particles consisting of 80.75% w/w of calcium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume
• the finished formulation comprises 50% of its gamma-hydroxybutyrate content in immediate-release particles consisting of 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns and 50% of its gamma-hydroxybutyrate content in modified release particles consisting of 10.5 % w/w of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns, layered with 56.5% w/w of calcium salt of gamma-hydroxybutyric acid mixed with 3% w/w of Povidone TM K30 and finally coated with a coating composition consisting of 18% w/w of hydrogenated vegetable oil (Lubritab TM or equivalent), 4% of methacrylic acid copolymer type C (Eudragit TM L100-55 or equivalent) and 8%
• the immediate release portion of the formulation can take any form capable of achieving an immediate release of the gamma-hydroxybutyrate when ingested.
• the formulation when the formulation is a particulate formulation, the formulation can include unmodified "raw" gamma-hydroxybutyrate, rapidly dissolving gamma-hydroxybutyrate granules, particles or microparticles comprised of a core covered by a gamma-hydroxybutyrate loaded layer containing a binder such as povidone.
• the preferred immediate release particles of gamma-hydroxybutyrate of the present invention comprises a core and a layer deposited on the core that contains the gamma-hydroxybutyrate.
• the core can be any particle chosen from the group consisting of:
• the core can also comprise other particles of pharmaceutically acceptable excipients such as particles of hydroxypropyl cellulose (such as Klucel TM from Aqualon Hercules), guar gum particles (such as Grinsted TM Guar from Danisco), xanthan particles (such as Xantural TM 180 from CP Kelco).
• particles of hydroxypropyl cellulose such as Klucel TM from Aqualon Hercules
• guar gum particles such as Grinsted TM Guar from Danisco
• xanthan particles such as Xantural TM 180 from CP Kelco.
• the cores are sugar spheres or microcrystalline cellulose spheres, such as Cellets TM 90, Cellets TM 100 or Cellets TM 127 marketed by Pharmatrans, or also Celphere TM CP 203, Celphere TM CP305, Celphere TM SCP 100.
• the core is a microcrystalline cellulose sphere.
• the core is a Cellets TM 127 from Pharmatrans.
• the core preferably has a mean volume diameter of about 95 to about 450 microns, preferably about 95 to about 170 microns, most preferably about 140 microns.
• the layer deposited onto the core comprises the immediate release gamma-hydroxybutyrate.
• the layer also comprises a binder, which can be chosen from the group consisting of:
• Low molecular weight hydroxypropyl cellulose corresponds to grades of hydroxypropyl cellulose having a molecular weight of less than 800,000 g/mol, preferably less than or equal to 400,000 g/mol, and in particular less than or equal to 100,000 g/mol.
• Low molecular weight hydroxypropyl methylcellulose (or hypromellose) corresponds to grades of hydroxypropyl methylcellulose the solution viscosity of which, for a 2% solution in water and at 20° C, is less than or equal to 1,000 mPa ⁇ s, preferably less than or equal to 100 mPa ⁇ s and in particular less than or equal to 15 mPa ⁇ s.
• Low molecular weight polyvinyl pyrrolidone corresponds to grades of polyvinyl pyrrolidone having a molecular weight of less than or equal to 1,000,000 g/mol, preferably less than or equal to 800,000 g/mol, and in particular less than or equal to 100,000 g/mol.
• the preferred binder is povidone K30 or K29/32, especially Plasdone TM K29/32 from ISP.
• the binder can be present in an amount of 0 to 80%, 0 to 70%, 0 to 60%, 0 to 50%, 0 to 40%, 0 to
• the preferred amount of binder is 5% of binder over the total mass of gamma-hydroxybutyrate and binder.
• the layer deposited on the core can represent at least 10% by weight, and even greater than 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90% by weight of the total weight of the immediate release particle of gamma-hydroxybutyrate. Most preferably, the layer deposited on the core represents about 85% of the weight of the immediate release particle of gamma-hydroxybutyrate.
• the immediate-release particles comprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 450 microns.
• the immediate-release particles comprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 170 microns.
• the polymer carrying free carboxylic groups is preferably selected from: (meth)acrylic acid/alkyl (meth)acrylate copolymers or methacrylic acid and methylmethacrylate copolymers or methacrylic acid and ethyl acrylate copolymers or methacrylic acid copolymers type A, B or C, cellulose derivatives carrying free carboxylic groups, preferably cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethylethyl cellulose, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, zein, shellac, alginate and mixtures thereof.
• the polymer carrying free carboxylic groups is selected from the group consisting of copolymers of methacrylic acid and ethyl acrylate 1:1, copolymers of methacrylic acid and methylmethacrylate 1:2, and mixtures thereof.
• the coating comprises a polymer carrying free carboxylic groups wherein the free carboxylic groups are substantially ionized at pH 7.5.
• the hydrophobic compound with a melting point equal or greater than 40°C can be selected from the group consisting of hydrogenated vegetable oils, vegetable waxes, wax yellow, wax white, wax microcrystalline, lanolin, anhydrous milk fat, hard fat suppository base, lauroyl macrogol glycerides, polyglyceryl diisostearate, diesters or triesters of glycerol with a fatty acid, and mixtures thereof.
• the hydrophobic compound with a melting point equal or greater than 40°C is chosen from the group of following products: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, candellila wax, tristearin, tripalmitin, trimyristin, yellow wax, hard fat or fat that is useful as suppository bases, anhydrous dairy fats, lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogol glycerides, polyglyceryl diisostearate, diethylene glycol monostearate, ethylene glycol monostearate, omega 3 fatty acids, and mixtures thereof.
• a particularly preferred subgroup of products comprises hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin, tripalmitin, trimyristin, beeswax, hydrogenated poly-1 decene, carnauba wax, and mixtures thereof.
• the hydrophobic compound with a melting point equal or greater than 40°C it is preferable the hydrophobic compound with a melting point equal or greater than 40°C to be chosen from the group of products sold under the following trademarks: Dynasan TM , Cutina TM , Hydrobase TM , Dub TM , Castorwax TM , Croduret TM , Compritol TM , Sterotex TM , Lubritab TM , Apifil TM , Akofine TM , Softisan TM , Hydrocote TM , Livopol TM , Super Hartolan TM , MGLA TM , Corona TM , Protalan TM , Akosoft TM , Akosol TM , Cremao TM , Massupol TM , Novata TM , Suppocire TM , Wecobee TM , Witepsol TM , Lanolin TM , Incromega TM , Esta
• a particularly suitable coating is composed of a mixture of hydrogenated vegetable oil and a methacrylic acid copolymer.
• Eudragit ® methacrylic acid copolymers namely the methacrylic acid - methyl methacrylate copolymers and the methacrylic acid - ethyl acrylate copolymers, have a pH-dependent solubility: typically, the pH triggering the release of the active ingredient from the microparticles is set by the choice and mixture of appropriate Eudragit ® polymers.
• the modified release particles of gamma-hydroxybutyrate consist of 10.5 % w/w of microcrystalline cellulose spheres with a volume mean diameter of about 95 microns to about 170 microns, layered with 56.5% w/w of gamma-hydroxybutyrate mixed with 3% w/w of Povidone TM K30 and finally coated with a coating composition consisting of 18% w/w of hydrogenated vegetable oil (Lubritab TM or equivalent), 4% of methacrylic acid copolymer type C (Eudragit TM L100-55 or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit TM S100 or equivalent), all percentages expressed based on the total weight of the final modified release particles of gamma-hydroxybutyrate.
• a coating composition consisting of 18% w/w of hydrogenated vegetable oil (Lubritab TM or equivalent), 4% of methacrylic acid copolymer type C (Eudragit TM L
• the invention provides a modified release formulation of gamma-hydroxybutyrate, comprising immediate release and modified release portions, wherein (a) the formulation releases at least 80% of its gamma-hydroxybutyrate at 1 hour when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C and a paddle speed of 75 rpm, (b) the formulation releases 40 to 65%, of its gamma-hydroxybutyrate at one hour and at three hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, (c) the formulation releases greater than 60% of its gamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus 2 according to USP 38 ⁇ 711> in 900 mL of 0.1N hydro
• Tables 1a-1d provide the qualitative and quantitative compositions of sodium oxybate IR microparticles, MR microparticles, and mixtures of IR and MR microparticles.
• the physical structure of the microparticles showing the qualitative and quantitative composition of the IR and MR microparticles is depicted in Figure 1 .
• sodium oxybate immediate release (IR) microparticles were prepared as follows: 1615.0 g of sodium oxybate and 85.0 g of polyvinylpyrrolidone (Povidone K30-Plasdone TM K29/32 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water. The solution was entirely sprayed onto 300 g of microcrystalline cellulose spheres (Cellets TM 127) in a fluid bed spray coater apparatus. IR Microparticles with volume mean diameter of about 270 microns were obtained.
• MR microparticles were prepared as follows: 22.8 g of methacrylic acid copolymer Type C (Eudragit TM L100-55), 45.8 g of methacrylic acid copolymer Type B (Eudragit TM S100), 102.9 g of hydrogenated cottonseed oil (Lubritab TM ), were dissolved in 1542.9 g of isopropanol at 78°C. The solution was sprayed entirely onto 400.0 g of the sodium oxybate IR microparticles described above in a fluid bed spray coater apparatus with an inlet temperature of 48° C, spraying rate around 11 g per min and atomization pressure of 1.3 bar. MR microparticles were dried for two hours with inlet temperature set to 56°C. MR microparticles with mean volume diameter of about 320 microns were obtained.
• the finished composition which contains a 50:50 mixture of MR and IR microparticles calculated on their sodium oxybate content, was prepared as follows: 353.36 g of the above IR microparticles, 504.80 g of the above MR microparticles, 14.27 g of malic acid (D/L malic acid), 6.34 g of xanthan gum (Xantural TM 75 from Kelco), 9.51 g of carrageenan gum (Viscarin TM PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose (Natrosol TM 250M from Ashland) and 4.51 g of magnesium stearate were mixed.
• Table 1a Composition of IR Microparticles Component Function Quantity per 2.25 g dose (g) Sodium oxybate Drug substance 2.25 Microcrystalline cellulose spheres Core 0.418 Povidone K30 Binder and excipient in diffusion coating 0.118 Ethyl alcohol Solvent Eliminated during processing Purified water Solvent Eliminated during processing Total 2.786
• Table 1b Composition of MR Microparticles Component Function Quantity per 4.5 g dose (g) IR Microparticles Core of MR microparticles 2.786 Hydrogenated Vegetable Oil Coating excipient 0.716 Methacrylic acid Copolymer Type C Coating excipient 0.159 Methacrylic acid Copolymer Type B Coating excipient 0.318 Isopropyl alcohol Solvent Eliminated during processing Total 3.981
• Table 1c Qualit
• IR microparticles were prepared by coating the IR microparticles described in example 1 with a top coat layer. Microparticles were prepared as follows: 170.0 of hydroxypropyl cellulose (Klucel TM EF Pharm from Hercules) were solubilized in 4080.0g of acetone. The solution was entirely sprayed onto 1530.0g of the IR microparticles of Example 1 in a fluid bed spray coater apparatus. IR Microparticles with volume mean diameter of about 298 microns were obtained (see Table 1bis-a).
• the finished composition which contains a 50:50 mixture of MR and IR microparticles based on their sodium oxybate content, was prepared as follows: 412.22g of the above IR microparticles, 530.00g of the above MR microparticles, 29.96g of malic acid (D/L malic acid), 4.96g of xanthan gum (Xantural TM 75 from Kelco), 4.96g of colloidal silicon dioxide (Aerosil TM 200 from Degussa) and 9.92g of magnesium stearate were mixed.
• Table 1bis-a Composition of IR Microparticles Component Function Quantity per 2.25 g dose (g) Sodium oxybate Drug substance 2.25 Microcrystalline cellulose spheres Core 0.418 Povidone K30 Binder and excipient in diffusion coating 0.118 Hydroxypropyl cellulose Top coat 0.310 Ethyl alcohol Solvent Eliminated during processing Purified water Solvent Eliminated during processing Acetone Solvent Eliminated during processing Total 3.096
• Table 1bis-b Qualitative Finished Composition Component Function Quantity per 4.5 g dose (g) MR microparticles Modified release fraction of sodium oxybate 3.981 IR microparticles Immediate release fraction of sodium oxybate 3.096 Malic acid Acidifying agent 0.225 Xanthan gum Suspending agent
• this alternative composition has the following characteristics: same MR microparticles, same IR microparticles but with a top coat, increased amount of malic acid, only one suspending agent (xanthan gum) and presence ofa glidant.
• EXAMPLE 2 IN VITRO RELEASE PROFILES OF IR, MR AND FINISHED COMPOSITIONS OF FORMULATIONS OF EXAMPLES 1 AND 1BIS
• MR microparticles from Example 1 49.1g were mixed with 0.5g of magnesium stearate (from Peter Graven) and 0.25g of colloidal silicon dioxide (Aerosil TM 200 from Evonik).
• the dissolution profile of 4040 mg of the mixture which corresponds to 2250 mg of sodium oxybate per vessel was determined using the USP apparatus 2. Dissolution medium temperature was maintained at 37.0 ⁇ 0.5 °C, and the rotating paddle speed was set at 75 rpm.
• the release profile of the MR microparticles is shown in Figure 3 and Table 2c.
• the sodium oxybate was not released in the 0.1N HCl dissolution medium during two hours. After the switch to pH 6.8 dissolution medium, all the sodium oxybate was released within 30 minutes.
• Table 2c Percent Sodium Oxybate Released in two sequential dissolution media (0.1HCl for 2 hours, then phosphate buffer pH 6.8) for MR microparticles of sodium oxybate prepared according to Example 1 Time (h) % released 0 0 1 1 2 2 2.25 33 2,5 97 3 103 4 104 6 103
• the dissolution profile of the quantity equivalent to 4.5g sodium oxybate of the finished composition according Example 1 was determined in 900 mL of deionized water using the USP apparatus 2.
• the dissolution medium was maintained at 37.0 ⁇ 0.5 °C and the rotating paddle speed was fixed at 50 rpm.
• the release profile is shown in Figure 5 and Table 2d.
• the IR fraction of sodium oxybate was solubilized in 15 minutes.
• the release of sodium oxybate from the modified-release fraction started after approximately 4 hours with 90% of the total dose released at 6 hours. Table 2d.
• Figure 7 and Table 2g depict dissolution profiles determined using a USP apparatus 2 in a 900 mL in 0.1N HCl dissolution medium of four finished compositions, two prepared according to Example 1 and two prepared according to Example 1bis.
• the dissolution medium was maintained at 37.0 ⁇ 0.5 °C and the rotating paddle speed was fixed at 100 rpm. It shows that the composition according to the invention releases from 10 to 65% of its sodium oxybate at 1 and 3 hours and releases greater than 60% at 10 hours.
• Example 1bis Example 1bis Example 1 Example 1 0 0 0 0 0 0.25 Nd Nd 52 50 0,5 51 50 Nd Nd 1 51 50 54 51 3 51 50 54 52 6 55 52 55 53 8 72 61 60 57 10 Nd Nd 73 70 12 86 90 85 83 16 88 96 96 94 20 Nd Nd 99 98 Nd: not determined
• Figure 8 and Table 2h depict dissolution profiles determined using a USP apparatus 2 in a 900 mL phosphate buffer pH 6.8 dissolution medium for four finished compositions prepared according to Example 1 or 1bis.
• the dissolution medium was maintained at 37.0 ⁇ 0.5 °C and the rotating paddle speed was fixed at 100 rpm. It shows that the composition according to the invention releases more than 80% of its sodium oxybate at 3 hours. Table 2h.
• Example 1bis Example 1bis Example 1 Example 1 0 0 0 0 0 0 0,25 Nd Nd 75 84 0,5 99 98 Nd Nd 1 101 101 100 102 1,5 101 101 106 108 2 100 100 Nd Nd 3 103 100 Nd Nd 4 103 100 Nd Nd 6 102 99 101 102 8 103 99 101 105 10 103 99 101 Nd 12 101 99 101 102 16 Nd Nd 100 101 20 Nd Nd 99 98 Nd: not determined
• Example 1 The finished composition of Example 1bis given as a 4.5 g once-nightly dose rather than a standard Xyrem ® dosing twice (2 x 2.25 g) nightly 4 hours apart, produced a dramatically different pharmacokinetic profile than Xyrem ® as shown in Figure 11 .
• Tables 3a and 3b 4.5 g nighttime doses of finished composition of the invention equivalent to twice-nightly doses of Xyrem ® (2 x 2.25 g) provided somewhat less total exposure to sodium oxybate with a later median T max than the initial Xyrem ® dose.
• the relative bioavailability was about 88%.
• composition according to the invention avoids the high second-dose peak concentration of Xyrem ® and therefore does not exhibit the substantial between-dose fluctuations in concentration, while achieving a comparable mean C 8h .
• Table 3a Pharmacokinetic Parameters of finished composition of Example 1bis vs.
• the pharmacokinetic profile of a single 6 g dose of finished composition produced according to Example 1bis was also tested and found to have a similar pharmacokinetic profile as the 4.5 g dose.
• Figure 12 provides a pharmacokinetic profile comparison of a single 4.5 g or 6 g dose of finished composition according to Example 1bis in the same 7 subjects.
• the pharmacokinetic profile for a 7.5 g dose of finished formulation produced according to Example 1bis was also obtained.
• Figure 13 and Table 3c provide data on a single 4.5 g, 6 g and 7.5 g dose, showing effects on T max , C max , C 8h , AUC 8h and AUC inf related to dose strength.
• the 7.5g dose achieved a mean C 8h equal to about 31 microgram/mL which represents approximately 128.5% of the C 8h obtained for Xyrem ® dosed 2 x 3.75g which was extrapolated to be approximately 24.07 microgram/mL from published data.
• the 7.5 g dose achieved a ratio of AUC 8h to AUC inf of about 0.89, whereas the ratio was 0.83 and 0.93 for the 4.5g and 6g doses respectively. Table 3c.
• Figure 14 and table 3d compare the pharmacokinetic parameters AUC inf and C 8h obtained for 7.5 g of a finished composition according to Example 1bis to the same parameters calculated for 2 x 4.5 g, i.e. 9 g total dose of Xyrem ® .
• the data show that a 7.5g dose of a formulation according to the invention given once nightly exhibits a similar PK profile to 9g of Xyrem ® given in two separate equal doses.
• Table 3d Table 3d.
• Tables 4a-4d provide the qualitative and quantitative compositions of IR microparticles, MR microparticles, and mixtures of IR and MR microparticles.
• the physical structure of the microparticles showing the qualitative and quantitative composition of the IR and MR microparticles is depicted in Figure 15 .
• sodium oxybate immediate release (IR) microparticle were prepared as follows: 1615.0g of Sodium Oxybate and 85.0g of polyvinylpyrrolidone (Povidone K30-Plasdone TM K29/32 from ISP) were solubilized in 1894.3g of absolute ethyl alcohol and 1262.9g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127) in a fluid bed spray coater apparatus. IR microparticles with volume mean diameter of about 270 microns were obtained.
• MR microparticles were prepared as follows: 4.0g of Methacrylic acid copolymer Type C (Eudragit TM L100-55), 49.3g of Methacrylic acid copolymer Type B (Eudragit TM S100), 80g of Hydrogenated cottonseed oil (Lubritab TM ), were dissolved in 1200.0g of isopropanol at 78°C. The solution was sprayed entirely on 400.0g of IR microparticles prepared above in a fluid bed spray coater apparatus with an inlet temperature 48°C, spraying rate around 11g per min and atomization pressure 1.3 bar. MR microparticles were dried for two hours with inlet temperature set to 56°C. MR microparticles with volume mean diameter of about 330 microns were obtained.
• the finished composition which contained a 50:50 mixture of MR and IR microparticles calculated on their sodium oxybate content, was prepared as follows: 27.86g of IR microparticles, 37.15g of MR microparticles, 1.13g of malic acid (D/L malic acid), 0.50g of xanthan gum (Xantural TM 75 from Kelco), 0.75g of carrageenan gum (Viscarin TM PH209 from FMC Biopolymer), 0.75g of hydroxyethylcellulose (Natrosol TM 250M from Ashland) and 0.34g of magnesium stearate were mixed.
• Table 4a Composition of IR Microparticles Component Function Quantity per 2.25 g dose (g) Sodium oxybate Drug substance 2.25 Microcrystalline cellulose spheres Core 0.418 Povidone K30 Binder and excipient in diffusion coating 0.118 Ethyl alcohol Solvent Eliminated during processing Purified water Solvent Eliminated during processing Total 2.786
• Table 4b Composition of MR Microparticles Component Function Quantity per 2.25 g dose (g) IR Microparticles Core of MR Microparticles 2.786 Hydrogenated Vegetable Oil Coating excipient 0.557 Methacrylic acid Copolymer Type C Coating excipient 0.028 Methacrylic acid Copolymer Type B Coating excipient 0.344 Isopropyl alcohol Solvent Eliminated during processing Total 3.715
• Table 4c Qualit
• IR microparticles were prepared by coating the IR microparticles described in example 4 with a top coat layer.
• IR Microparticles were prepared as follows: 170.0 of hydroxypropyl cellulose (Klucel TM EF Pharm from Hercules) were solubilized in 4080.0g of acetone. The solution was entirely sprayed onto 1530.0g of the IR microparticles of Example 4 in a fluid bed spray coater apparatus. IR Microparticles with volume mean diameter of about 298 microns were obtained (see Table 4bis-a).
• the finished composition which contains a 50:50 mixture of MR and IR microparticles calculated based on sodium oxybate content, was prepared as follows: 424.99g of the above IR microparticles, 509.98g of the above MR microparticles, 30.89g of malic acid (D/L malic acid), 4.93g of xanthan gum (Xantural TM 75 from Kelco), 4.93g of colloidal silicon dioxide (Aerosil TM
• Table 4bis-a Composition of IR Microparticles Component Function Quantity per 2.25 g dose (g) Sodium oxybate Drug substance 2.25 Microcrystalline cellulose spheres Core 0.418 Povidone K30 Binder and excipient in diffusion coating 0.118 Hydroxypropyl cellulose Top coat 0.310 Ethyl alcohol Solvent Eliminated during processing Purified water Solvent Eliminated during processing Acetone Solvent Eliminated during processing Total 3.096
• Table 4bis-b Qualitative Finished Composition Component Function Quantity per 4.5 g dose (g) MR microparticles Modified release fraction of sodium oxybate 3.715 IR microparticles Immediate release fraction of sodium oxybate 3.096 Malic acid Acidifying agent 0.225 Xanthan gum Suspending agent 0.036 Colloidal silicon dioxide Gliding agent 0.036 Magnesium stearate Lubricant 0.072 Total 7.180
• Table 4bis-c Quantitative finished composition Component Function Quantity per 4.5 g dose (g) Sodium
• Figure 20 and Table 5c depict dissolution profiles determined using a USP apparatus 2 in a 900 mL in 0.1N HCl dissolution medium of three finished compositions prepared according to Example 4bis.
• the dissolution medium was maintained at 37.0 ⁇ 0.5 °C and the rotating paddle speed was fixed at 100 rpm. It shows that the composition according to the invention releases from 10 to 65% of its sodium oxybate at 1 and 3 hours and releases greater than 60% at 10 hours.
• Table 5c depict dissolution profiles determined using a USP apparatus 2 in a 900 mL in 0.1N HCl dissolution medium of three finished compositions prepared according to Example 4bis.
• the dissolution medium was maintained at 37.0 ⁇ 0.5 °C and the rotating paddle speed was fixed at 100 rpm. It shows that the composition according to the invention releases from 10 to 65% of its sodium oxybate at 1 and 3 hours and releases greater than 60% at 10 hours.
• Table 5c depict dissolution profiles determined using a USP apparatus 2 in a 900 mL
• Figure 21 and Table 5d depict dissolution profile determined using a USP apparatus 2 in a 900 mL phosphate buffer pH 6.8 dissolution medium for a finished composition prepared according to Example 4bis.
• the dissolution medium was maintained at 37.0 ⁇ 0.5 °C and the rotating paddle speed was set at 100 rpm. It shows that the composition according to the invention releases more than 80% of its sodium oxybate at 3 hours.
• Table 5d Percent Sodium Oxybate Released in phosphate buffer pH 6.8 Dissolution Medium for finished composition prepared according to Example 4bis Time (Hour)
• Example 4bis 0 0 0,25 54 0,5 54 0,75 55 1,0 56 1,5 63 2 77 3 103 4 105 6 105 8 102 10 101 12 104 16 100
• composition according to the invention avoids the high second-dose peak concentration of Xyrem ® and therefore does not exhibit the substantial between-dose fluctuations in concentration, while achieving a comparable mean C 8h .
• Table 6a Pharmacokinetic Parameters of finished composition of Example 4bis vs.
• the 4.5g dose achieved a mean C 8h equal to about 6.85 microgram/mL which represents approximately 74.1% of the C 8h obtained for Xyrem ® dosed 2 x 2.25g.
• the ratio of AUC 8h to AUC inf was about 0.89.
• Tables 7a-7c provide the qualitative and quantitative compositions of the MR microparticles, and mixtures of IR and MR microparticles.
• the physical structure of the microparticles showing the qualitative and quantitative composition of the IR and MR microparticles is depicted in Figure 23 .
• IR microparticles sodium oxybate immediate release (IR) microparticles were prepared according to Example 1bis.
• IR immediate release
• MR Sodium oxybate modified release microparticles were prepared in two steps:
• the finished composition which contains a 60:40 mixture of MR and IR microparticles calculated based on their sodium oxybate content, was prepared as follows: 326.69g of the above IR microparticles, 735.04g of the above MR microparticles, 23.74g of malic acid (D/L malic acid), 5.54g of xanthan gum (Xantural TM 75 from Kelco), 5.54g of colloidal silicon dioxide (Aerosil TM 200 from Degussa) and 11.08g of magnesium stearate were mixed. Individual samples of 8.40g (corresponding to a 4.5g dose of sodium oxybate with 40% of the dose as immediate-release fraction and 60% of the dose as modified release fraction) were weighed.
• Table 7a Composition of MR Microparticles Component Function Quantity per 2.25 g dose (g) IR Microparticles Core of MR Microparticles 2.786 Ethylcellulose 20 Coating excipient 0.743 Povidone K30 Coating excipient 0.074 Polyoxyl 40 Hydrogenated Castor Oil Coating excipient 0.037 Castor oil Coating excipient 0.074 Hydrogenated Vegetable Oil Coating excipient 0.557 Methacrylic acid Copolymer Type C Coating excipient 0.124 Methacrylic acid Copolymer Type B Coating excipient 0.248 Ethyl alcohol Solvent Eliminated during processing Acetone Solvent Eliminated during processing Water Solvent Eliminated during processing Isopropyl alcohol Solvent Eliminated during processing Total 4.644
• Table 7b Qualitative Composition of Finished Composition Component Function Quantity per 4.5 g dose (g) MR microparticles Modified release fraction of sodium oxybate 5.573 IR microparticles Immedi
• Table 7d Dissolution profile obtained for the MR microparticles of Example 7 in two sequential dissolution media (0.1N HCl for 2 hours then phosphate buffer pH 6.8) Time (hour)
• Example 7 0 0 1 0 2 1 2.25 5 2.5 44 3 74 64 89 6 96
• the finished composition of Comparative Example 7 was tested in the same pharmacokinetic study than the finished composition of Example 1 and 4. As summarized below (Tables 7e), 4.5 g nighttime dose of finished composition of the comparative Example 7 compared to twice-nightly doses of Xyrem ® (2 x 2.25 g) provided much less total exposure to sodium oxybate with a relative bioavailability of 67%. Table 7e. Pharmacokinetic Parameters of finished composition of Comparative Example 7 vs.
• Table 7g provides data on a single 4.5 g, 6 g and 7.5 g dose, showing effects on C max , C 8h , AUC 8h and AUC inf related to dose strength. Table 7g.
• Example 8.1 Modified release formulation of gamma-hydroxybutyrate comprising immediate release microparticles of potassium salt of gamma-hydroxybutyric acid and modified release microparticles of sodium salt of gamma-hydroxybutyric acid (sodium oxybate).
• Immediate release (IR) microparticles of potassium salt of gamma-hydroxybutyric acid can be prepared as follows: 1615.0 g of potassium salt of gamma-hydroxybutyric acid and 85.0 g of polyvinylpyrrolidone (Povidone K30- Plasdone TM K29/32 from ISP) are solubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water. The solution is entirely sprayed onto 300 g of microcrystalline cellulose spheres (Cellets TM 127) in a fluid bed spray coater apparatus.
• Immediate release (IR) microparticles of sodium salt of gamma-hydroxybutyric acid were prepared as follows: 1615.0g of sodium salt of gamma-hydroxybutyric acid and 85.0g of polyvinylpyrrolidone (Povidone K30 - Plasdone K29/32 from ISP) were solubilized in 1894.3g of absolute ethyl alcohol and 1262.9g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans Sanaq) in a fluid bed spray coater apparatus.
• MR microparticles are prepared as follows: 22.8 g of methacrylic acid copolymer Type C (Eudragit TM L100-55), 45.8 g of methacrylic acid copolymer Type B (Eudragit TM S100), 102.9 g of hydrogenated cottonseed oil (Lubritab TM ), are dissolved in 1542.9 g of isopropanol at 78°C. The solution is sprayed entirely onto 400.0 g of the sodium oxybate IR microparticles described above in a fluid bed spray coater apparatus with an inlet temperature of 48° C, spraying rate around 11 g per min and atomization pressure of 1.3 bar. MR microparticles are dried for two hours with inlet temperature set to 56°C. MR microparticles with mean volume diameter of about 320 microns were obtained.
• the finished formulation which contains a 50:50 mixture of MR and IR microparticles calculated on their gamma-hydroxybutyrate content, can be prepared as follows: 398.51 g of the above IR microparticles, 504.80 g of the above MR microparticles, 16.09 g of D/L malic acid, 6.34 g of xanthan gum (Xantural TM 75 from Kelco), 9.51 g of carrageenan gum (Viscarin TM PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose (Natrosol TM 250M from Ashland) and 4.75 g of magnesium stearate were mixed.
• Table 8a Composition of IR Microparticles of gamma-hydroxybutyrate of example 8.1 Component Function Quantity per 2.25 g dose (g) Potassium salt of hydroxybutyric acid Drug substance 2.537 Microcrystalline cellulose spheres Core 0.471 Povidone K30 Binder and excipient in diffusion coating 0.134 Ethyl alcohol Solvent Eliminated during processing Purified water Solvent Eliminated during processing Total 3.142
• Table 8b Composition of MR Microparticles of gamma-hydroxybutyrate of example 8.1 Component Function Quantity per 2.25 g dose (g) Sodium oxybate Drug substance 2.25 Povidone K30 Binder 0.118 Microcrystalline cellulose spheres Core 0.419 Hydrogenated Vegetable Oil Coating excipient 0.717 Methacrylic acid Copolymer Type
• Example 8.2 Modified release formulation of gamma-hydroxybutyrate comprising immediate release microparticles of potassium salt of gamma-hydroxybutyric acid, immediate release microparticles of magnesium salt of gamma-hydroxybutyric acid, immediate release microparticles of calcium salt of gamma-hydroxybutyric acid and modified release microparticles of sodium salt of gamma-hydroxybutyric acid (sodium oxybate).
• Immediate release (IR) microparticles of potassium salt of gamma-hydroxybutyric acid are prepared according to example 8.1.
• Immediate release (IR) microparticles of magnesium salt of gamma-hydroxybutyric acid or calcium salt of gamma-hydroxybutyric acid can be prepared using the same manufacturing process by replacing the potassium salt of gamma-hydroxybutyric acid by the same weight of respectively magnesium salt of gamma-hydroxybutyric acid or calcium salt of gamma-hydroxybutyric acid.
• the finished formulation which contains a 50:50 mixture of MR and IR microparticles calculated on their gamma-hydroxybutyrate content, can be prepared as follows: 132.84 g of the IR microparticles of potassium salt of gamma-hydroxybutyric acid, 215.32 g of the IR microparticles of magnesium salt of gamma-hydroxybutyric acid, 230.05 g of the IR microparticles of calcium salt of gamma-hydroxybutyric acid, 504.80 g of the MR microparticles of sodium oxybate, 23.35 g of D/L malic acid, 6.34 g of xanthan gum (Xantural TM 75 from Kelco), 9.51 g of carrageenan gum (Viscarin TM PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose (Natrosol TM 250M from Ashland) and 5.69 g of magnesium stearate were mixed.
• EXAMPLE 8.3 MODIFIED RELEASE FORMULATION OF GAMMA-HYDROXYBUTYRATE COMPRISING IMMEDIATE RELEASE MICROPARTICLES OF POTASSIUM SALT OF GAMMA-HYDROXYBUTYRIC ACID AND MODIFIED RELEASE MICROPARTICLES OF CALCIUM SALT OF GAMMA-HYDROXYBUTYRIC ACID.
• the solution is sprayed entirely onto 400.0 g of the immediate release microparticles of calcium salt of gamma-hydroxybutyric acid described above in a fluid bed spray coater apparatus with an inlet temperature of 48° C, spraying rate around 11 g per min and atomization pressure of 1.3 bar.
• MR microparticles are dried for two hours with inlet temperature set to 56°C.
• the finished formulation which contains a 50:50 mixture of MR and IR microparticles calculated on their gamma-hydroxybutyrate content, can be prepared as follows: 398.53 g of the IR microparticles of potassium salt of gamma-hydroxybutyric acid, 492.87 g of the MR microparticles of sodium oxybate, 16.10 g of D/L malic acid, 6.34 g of xanthan gum (Xantural TM 75 from Kelco), 9.51 g of carrageenan gum (Viscarin TM PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose (Natrosol TM 250M from Ashland) and 4.69 g of magnesium stearate were mixed.
• IR particles were prepared as follows: 1615.0g of Sodium Oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone - Plasdone TM K30 from ISP) were solubilized in 1894.3g of absolute ethyl alcohol and 1262.9g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 268 microns were obtained.
• MR coated particles were prepared as follows: 39.9g of Methacrylic acid copolymer Type C (Eudragit TM L100-55 from Evonik), 80.1g of Methacrylic acid copolymer Type B (Eudragit TM S100 from Evonik), 180.0g of Hydrogenated cottonseed oil (Lubritab TM from JRS), were dissolved in 2700.0g of isopropanol at 78°C. The solution was sprayed entirely on 700.0g of IR particles in a fluid bed spray coater apparatus Glatt TM G.P.C.G.1.1 with inlet temperature 49°C, spraying rate around 11.6g per min and atomization pressure 1.6 bar. MR microparticles were dried for 2 hours with inlet temperature set to 56°C. Sodium oxybate MR coated particles with mean diameter of 324 microns were obtained.
• the finished composition which contains a 50:50 mixture of MR and IR particles calculated on their sodium oxybate content, was prepared as follows: 655.1g of the above IR particles, 936.4g of the above MR particles, 26.5g of Malic acid (D/L malic acid regular from Bartek), 11.7g of xanthan gum (Xantural TM 75 from CP Kelco), 17.6g of carragenan gum (Viscarin TM PH209 from FMC Biopolymer), 17.6g of hydroxyethylcellulose (Natrosol TM 250M from Ashland ) and 8.2g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.11g (corresponding to a 4.5g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• Figure 29 and Table 9a below depict dissolution profiles determined in 0.1N HCl using a USP apparatus 2.
• the dissolution medium was maintained at 37.0 ⁇ 0.5°C and the rotating paddle speed was fixed at 75 rpm.
• Single dose units were poured in a container containing 50 mL of tap water. After 5 and 15 minutes, the suspension was poured in the dissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10 mL of water were used to rinse the container and were added to the dissolution vessel.
• IR particles were prepared as follows: 1615.0g of Sodium Oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone - Plasdone TM K30 from ISP) were solubilized in 1894.3g of absolute ethyl alcohol and 1262.9g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 273 microns were obtained.
• MR coated particles were prepared as follows: 39.9g of Methacrylic acid copolymer Type C (Eudragit TM L100-55 from Evonik), 80.1g of Methacrylic acid copolymer Type B (Eudragit TM S100 from Evonik), 180.0g of Hydrogenated cottonseed oil (Lubritab TM from JRS), were dissolved in 2700.0g of isopropanol at 78°C. The solution was sprayed entirely on 700.0g of IR particles in a fluid bed spray coater apparatus Glatt TM G.P.C.G.1.1 with inlet temperature 47°C, spraying rate around 10.7g per min and atomization pressure 1.6 bar. MR microparticles were dried for 2 hours with inlet temperature set to 60°C. Sodium oxybate MR coated particles with mean diameter of 309 microns were obtained.
• the finished composition which contains a 50:50 mixture of MR and IR particles calculated on their sodium oxybate content, was prepared as follows: 100.0g of the above IR particles, 142.9g of the above MR particles, 2.0g of Malic acid (D/L malic acid regular from Bartek), 1.2g of xanthan gum (Xantural TM 75 from CP Kelco), 1.2g of hydrophilic fumed silica (Aerosil TM 200 from Degussa) and 2.5g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 6.93g (corresponding to a 4.5g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• Figure 30 and Table 9b below depict dissolution profiles determined in 0.1N HCl using a USP apparatus 2.
• the dissolution medium was maintained at 37.0 ⁇ 0.5°C and the rotating paddle speed was fixed at 75 rpm.
• Single dose units were poured in a container containing 50 mL of tap water. After 5 and 15 minutes, the suspension was poured in the dissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10 mL of water were used to rinse the container and were added to the dissolution vessel.
• Table 9b Time (h) % dissolved 5 min reconstitution time % dissolved 15 min reconstitution time 0 0 0 0,25 51 51 1 51 52 3 51 53 6 52 62 8 60 86 10 77 96 12 90 98 16 98 98 98
• IR particles were prepared as follows: 1615.0g of Sodium Oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone - Plasdone TM K30 from ISP) were solubilized in 1894.3g of absolute ethyl alcohol and 1262.9g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 255 microns were obtained.
• the finished composition which contains a 50:50 mixture of MR and IR particles calculated on their sodium oxybate content, was prepared as follows: 36.2g of the above IR particles, 51.8g of the above MR particles, 16.1g of Malic acid (D/L malic acid regular from Bartek), 0.7g of xanthan gum (Xantural TM 75 from CP Kelco), 1.0g of carragenan gum (Viscarin TM PH209 from FMC Biopolymer), 1.0g of hydroxyethylcellulose (Natrosol TM 250M from Ashland ) and 0.6g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 8.25g (corresponding to a 4.5g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• the solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1.
• Sodium oxybate IR particles with mean diameter of 271 microns were obtained.
• MR coated particles were prepared as follows: 39.9g of methacrylic acid copolymer type C (Eudragit TM L100-55 from Evonik), 80.1g of methacrylic acid copolymer type B (Eudragit TM S100 from Evonik), 180.0g of hydrogenated cottonseed oil (Lubritab TM from JRS), were dissolved in 2700.0g of isopropanol at 78°C. The solution was sprayed entirely on 700.0g of sodium oxybate IR particles in a fluid bed spray coater apparatus Glatt TM G.P.C.G.1.1 with inlet temperature 48°C, spraying rate around 11.5g per min and atomization pressure 1.6 bar. MR coated particles were dried for 2 hours with inlet temperature set to 56°C. MR particles of sodium oxybate with mean diameter of 321 microns were obtained.
• the finished composition which contains a 50:50 mixture of MR and IR sodium oxybate particles calculated on their sodium oxybate content, was prepared as follows: 634.0g of the above IR particles, 907.6g of the above MR particles, 25.7g of malic acid (D/L malic acid regular from Bartek), 11.4g of xanthan gum (Xantural TM 75 from CP Kelco), 17.1g of carragenan gum (Viscarin TM PH209 from FMC Biopolymer), 17.1g of hydroxyethylcellulose (Natrosol TM 250M from Ashland ) and 8.1g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 14.20g (corresponding to a 9g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• Figure 32 and Table 10a below depict dissolution profiles of 9g doses determined using a USP apparatus 2 in 0.1N HCl.
• the dissolution medium was maintained at 37.0 ⁇ 0.5°C and the rotating paddle speed was fixed at 75 rpm.
• Single dose units were poured in a container containing 50 mL of tap water. After 5 minutes, the suspension was poured in the dissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10 mL of water were used to rinse the container and were added to the dissolution vessel.
• Dissolution profile was determined with and without rinsing step. Table 10a Time (h) with rinsing without rinsing 0 0 0 0,25 47 46 1 51 51 3 53 52 6,0 54 53 8 61 60 10 77 74 12 91 88 16 98 95 20 98 96
• Example 11a 15% IR / 85% IR with MR pH*6.5 microparticles
• Table 11c Component Function Quantity per 4.5 g dose (g) MR microparticles Modified release fraction of sodium oxybate 6.767 IR microparticles Immediate release fraction of sodium oxybate 0.836 Malic acid Acidifying agent 0.034 Xanthan gum Suspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant 0.039 Total 7.876
• IR particles were prepared as follows: 1615.1g of sodium oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone - Plasdone TM K30 from ISP) were solubilized in 1903.2g of absolute ethyl alcohol and 1267.1g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 268 microns were obtained.
• IR particles were prepared as follows: 1615.0g of sodium oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone - Plasdone TM K30 from ISP) were solubilized in 1894.3g of absolute ethyl alcohol and 1262.9g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 270 microns were obtained.
• MR coated particles were prepared as follows: 22.8g of methacrylic acid copolymer type C (Eudragit TM L100-55 from Evonik), 45.8g of methacrylic acid copolymer type B (Eudragit TM S100 from Evonik), 102.9g of hydrogenated cottonseed oil (Lubritab TM from JRS), were dissolved in 1543.1g of isopropanol at 78°C. The solution was sprayed entirely on 400.0g of IR particles in a fluid bed spray coater apparatus Glatt TM G.P.C.G.1.1 with inlet temperature 47°C, spraying rate around 10.8g per min and atomization pressure 1.3 bar. MR coated particles were dried for 2 hours with inlet temperature set to 56°C. Sodium oxybate MR coated particles with mean diameter of 330 microns were obtained.
• Example 11a for the dissolution profile of the MR microparticles.
• Table 11i Component Function Quantity per 4.5 g dose (g) MR microparticles Modified release fraction of sodium oxybate 2.786 IR microparticles Immediate release fraction of sodium oxybate 3.622 Malic acid Acidifying agent 0.110 Xanthan gum Suspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant 0.034 Total 6.752
• the finished composition which contains a 85:15 mixture of sodium oxybate MR and IR particles calculated on their sodium oxybate content, can be prepared as follows: 100.0g of the above IR particles, 76.9g of the above MR coated particles, 3.0g of Malic acid (D/L malic acid regular from Bartek), 1.4g of xanthan gum (Xantural TM 75 from CP Kelco), 2.1g of carragenan gum (Viscarin TM PH209 from FMC Biopolymer), 2.1g of hydroxyethylcellulose (Natrosol TM 250M from Ashland ) and 0.9g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 6.75g (corresponding to a 4.5g dose with 65% of the dose as immediate-release fraction and 35% of the dose as modified release fraction) were weighed.
• Dissolution profile After reconstitution with 50 ml tap water and rinsing with 10 ml of tap water, the finished composition will display the dissolution profiles in Figures 39 and 40 and Tables 11j and 11k in 840ml of 0.1N HCl and in pH 6.8 phosphate buffer (0.05M monobasic potassium phosphate solution - pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2, at 37.0 ⁇ 0.5°C and the rotating paddle speed at 75 rpm.
• pH 6.8 phosphate buffer 0.05M monobasic potassium phosphate solution - pH adjusted to 6.8 with 5N NaOH
• the dissolution profile in pH 6.8 phosphate buffer of the finished composition is expected to be similar to the profile depicted in Figure 8 , insofar as the MR particles are similar and only the nature of the immediate-release fraction was changed.
• the finished composition which contains a 50:50 mixture of MR and IR sodium oxybate particles calculated on their sodium oxybate content, was prepared as follows: 67.4g of the above IR particles obtained by extrusion-spheronization, 115.6g of the above MR coated particles, 3.3g of malic acid (D/L malic acid regular from Bartek), 0.9g of xanthan gum (Xantural TM 75 from CP Kelco), 0.9g of hydrophilic fumed silica (Aerosil 200 from Degussa) and 1.9g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 6.54g (corresponding to a 4.5g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• MR coated particles were prepared as follows: 17.1g of methacrylic acid copolymer type C (Eudragit L100-55 from Evonik), 34.3g of methacrylic acid copolymer type B (Eudragit S100 from Evonik), 77.1g of hydrogenated cottonseed oil (Lubritab from JRS), are dissolved in 1157.9g of isopropanol at 78°C. The solution is sprayed entirely on 300.0g of IR particles prepared above in a fluid bed spray coater apparatus Glatt G.P.C.G.1.1 with inlet temperature 48°C, spraying rate around 10.7g per min and atomization pressure 1.3 bar. MR microparticles were dried for 2 hours with inlet temperature set to 56°C. Sodium oxybate MR coated particles with mean diameter of 289 microns are obtained.
• Table 13c Component Function Quantity per 4.5 g dose (g) MR microparticles Modified release fraction of sodium oxybate 3.841 IR microparticles Immediate release fraction of sodium oxybate 2.647 Malic acid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant 0.034 Total 6.835
• the finished composition After reconstitution with 50ml of tap water and rinsing with 10ml of tap water, the finished composition is expected to provide the following dissolution profiles in Figures 46 and 47 and Tables 13d and 13e in 840ml of 0.1N HCl and pH6.8 phosphate buffer (0.05M monobasic potassium phosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2, at 37.0 ⁇ 0.5°C and the rotating paddle speed at 75 rpm.
• 0.1N HCl and pH6.8 phosphate buffer 0.05M monobasic potassium phosphate solution with pH adjusted to 6.8 with 5N NaOH
• EXAMPLE 14 MR PARTICLES WITH LARGER CORE SIZE (160 MICRONS).
• MR coated particles were prepared as follows: 25.7g of methacrylic acid copolymer type C (Eudragit TM L100-55 from Evonik), 51.5g of methacrylic acid copolymer type B (Eudragit TM S100 from Evonik), 115.7g of hydrogenated cottonseed oil (Lubritab TM from JRS), were dissolved in 1735.7g of isopropanol at 78°C. The solution was sprayed entirely on 450.0g of IR particles in a fluid bed spray coater apparatus Glatt TM G.P.C.G.1.1 with inlet temperature 47°C, spraying rate around 9.6g per min and atomization pressure 1.6 bar. MR particles were dried for 2 hours with inlet temperature set to 56°C. Sodium oxybate MR coated particles with mean diameter of 370 microns were obtained.
• Table 14c Component Function Quantity per 4.5 g dose (g) MR microparticles Modified release fraction of sodium oxybate 2.786 IR microparticles Immediate release fraction of sodium oxybate 3.981 Malic acid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant 0.037 Total 7.115
• the finished composition is expected to provide the dissolution profiles in Figures 49 and 50 and Table 14d and 14e in 840ml of 0.1N HCl and in pH6.8 phosphate buffer (0.05M monobasic potassium phosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2, at 37.0 ⁇ 0.5°C and the rotating paddle speed at 75 rpm.
• Figure 53 and Table 15c below depict dissolution profiles determined using a USP apparatus 2 in 0.1N HCl.
• the dissolution medium was maintained at 37.0 ⁇ 0.5°C and the rotating paddle speed was fixed at 75 rpm.
• Single dose units were poured in a container containing 50 mL of tap water. After 5 minutes, the suspension was poured in the dissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10 mL of water were used to rinse the container and were added to the dissolution vessel.
• Table 15c Time (hour) % dissolved 0 0 0,25 45 1 52 2 92 3 94 4 97 6 97 8 97 10 96
• MR coated particles were prepared as follows: 37.6g of Methacrylic acid copolymer Type C (Eudragit TM L100-55 from Evonik), 75.4g of Methacrylic acid copolymer Type B (Eudragit TM S100 from Evonik), 48.5g of Hydrogenated cottonseed oil (Lubritab TM from JRS), were dissolved in 1458.0g of isopropanol at 78°C. The solution was sprayed entirely on 300.0g of IR particles in a fluid bed spray coater apparatus Glatt TM G.P.C.G.1.1 with inlet temperature 48°C, spraying rate around 11.7g per min and atomization pressure 1.6 bar. MR microparticles were dried for 2 hours with inlet temperature set to 56°C. Sodium oxybate MR coated particles with mean diameter of 491 microns were obtained.
• Dissolution data - 0.1N HCl Time (hour) % dissolved 0 0 0,25 3 1 3 3 45 4 77 6 96 8 98 10 98 Table 15e.Dissolution data - 50mM pH 6.8 phosphate buffer Time (h) % dissolved 0 0 0,25 1 0,5 22 0,75 87 1 98 2 97
• the finished composition is expected to exhibit the dissolution profiles in Figures 55 and 56 and Tables 15g and 15h in 0.1N HCl and in pH6.8 phosphate buffer (0.05M monobasic potassium phosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2, at 37.0 ⁇ 0.5°C and the rotating paddle speed at 75 rpm.
• IR pellets were prepared as follows: 1615.0g of Sodium Oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone - Plasdone TM K30 from ISP) were solubilized in 1903.2g of absolute ethyl alcohol and 1267.1g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 268 microns were obtained.
• MR coated particles were prepared as follows: 40.6g of Methacrylic acid copolymer Type C (Eudragit TM L100-55 from Evonik), 80.1g of Methacrylic acid copolymer Type B (Eudragit TM S100 from Evonik), 80.5g of Hydrogenated cottonseed oil (Lubritab TM from JRS), were dissolved in 1799.4g of isopropanol at 78°C. The solution was sprayed entirely on 300.0g of IR particles in a fluid bed spray coater apparatus Glatt TM G.P.C.G.1.1 with inlet temperature 48°C, spraying rate around 10.5g per min and atomization pressure 1.3 bar. MR microparticles were dried for 2 hours with inlet temperature set to 56°C. Sodium oxybate MR coated particles with mean diameter of 348 microns were obtained.
• the finished composition which contains a 50:50 mixture of MR and IR particles calculated on their sodium oxybate content, was prepared as follows: 156.0g of the above IR particles, 260.0g of the above MR coated particles, 6.3g of malic acid (D/L malic acid regular from Bartek), 2.8g of xanthan gum (Xantural TM 75 from CP Kelco), 4.2g of carragenan gum (Viscarin TM PH209 from FMC Biopolymer), 4.2g of hydroxyethylcellulose (Natrosol TM 250M from Ashland ) and 2.2g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.78g (corresponding to a 4.5g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• MR coated particles were prepared as follows: 20.0g of Methacrylic acid copolymer Type C (Eudragit TM L100-55 from Evonik), 40.0g of Methacrylic acid copolymer Type B (Eudragit TM S100 from Evonik), 40.0g of candelilla wax (Kahlwax TM 2039L from Brenntag), were dissolved in 904.0g of isopropanol at 78°C. The solution was sprayed entirely on 400.0g of IR particles in a fluid bed spray coater apparatus Glatt TM G.P.C.G.1.1 with inlet temperature 48°C, spraying rate around 10.9g per min and atomization pressure 1.3 bar. MR microparticles were dried for 2 hours with inlet temperature set to 56°C. Sodium oxybate MR coated particles with mean diameter of 302 microns were obtained.
• Table 161 Component Function Quantity per 4.5 g dose (g) MR microparticles Modified release fraction of sodium oxybate 3.483 IR microparticles Immediate release fraction of sodium oxybate 2.786 Malic acid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant 0.033 Total 6.615
• the finished composition which contains a 50:50 mixture of MR and IR particles calculated on their sodium oxybate content, was prepared as follows: 122.7g of the above IR particles, 153.2g of the above MR coated particles, 5.0g of malic acid (D/L malic acid regular from Bartek), 2.2g of xanthan gum (Xantural TM 75 from CP Kelco), 3.3g of carragenan gum (Viscarin TM PH209 from FMC Biopolymer), 3.3g of hydroxyethylcellulose (Natrosol TM 250M from Ashland ) and 1.5g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 6.62g (corresponding to a 4.5g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• Figures 70 and Table 16m depict dissolution profiles determined using a USP apparatus 2 in 0.1N HCl.
• the dissolution medium was maintained at 37.0 ⁇ 0.5°C and the rotating paddle speed was fixed at 75 rpm.
• Single dose units were poured in a container containing 50 mL of tap water. After 5 minutes, the suspension was poured in the dissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10 mL of water were used to rinse the container and were added to the dissolution vessel.
• Example 16d 60% Cetyl alcohol (Kolliwax TM CA)
• IR particles were prepared as follows: 1615.1g of Sodium Oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone - Plasdone TM K30 from ISP) were solubilized in 1898.7g of absolute ethyl alcohol and 1262.9g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 272 microns were obtained.
• IR particles were prepared as follows: 1615.0g of Sodium Oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone - Plasdone TM K30 from ISP) were solubilized in 1894.3g of absolute ethyl alcohol and 1262.9g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 285 microns were obtained.
• Sodium oxybate IR seal-coated particles were prepared by coating the IR particles described above with a seal-coat layer: 170.0g of hydroxypropylcellulose (Klucel TM EF Pharm from Hercules) were solubilized in 4080.0g of acetone. The solution was entirely sprayed onto 1530.0g of the above IR particles in a fluid bed spray coater apparatus. Sodium oxybate IR particles with volume mean diameter of about 298 microns were obtained.
• the finished composition which contains a 50:50 mixture of MR and IR particles calculated on their sodium oxybate content, was prepared as follows: 425.0g of the above IR seal-coated particles, 510.0g of the above MR coated particles, 30.9g of malic acid (D/L malic acid regular from Bartek), 4.9g of xanthan gum (Xantural TM 180 from CP Kelco), 4.9g of Aerosil TM 200 (amorphous anhydrous colloidal silicon dioxide from Evonik) and 9.9g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.18g (corresponding to a 4.5g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• Figure 75 and Table 17c depict the dissolution profile determined using a USP apparatus 2 in phosphate buffer pH 6.8 (0.05M monobasic potassium phosphate solution - pH adjusted to 6.8 with 5N NaOH).
• the dissolution medium was maintained at 37.0 ⁇ 0.5°C and the rotating paddle speed was fixed at 100 rpm.
• Single dose units were poured in a container containing 50 mL of tap water. After 5 minutes, the suspension was poured in the dissolution vessel containing 840 mL of pH 6.8 dissolution medium. 10 mL of water were used to rinse the container and were added to the dissolution vessel.
• Table 17c Time (hour) % dissolved 0 0 0,25 50 1 51 3 54 4 56 6 93 8 99 10 100 12 100 16 97
• Example 17b 100% Eudragit TM L100-55
• the finished composition which contains a 50:50 mixture of MR and IR particles calculated on their sodium oxybate content, was prepared as follows: 153.3g of the above IR particles, 219.0g of the above MR coated particles, 6.2g of malic acid (D/L malic acid regular from Bartek), 2.8g of xanthan gum (Xantural TM 75 from CP Kelco), 4.1g of carragenan gum (Viscarin TM PH209 from FMC Biopolymer), 4.1g of hydroxyethylcellulose (Natrosol TM 250M from Ashland ) and 1.9g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.12g (corresponding to a 4.5g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• Figure 77 and Table 17f depict dissolution profiles determined using a USP apparatus 2 in 0.1N HCl.
• the dissolution medium was maintained at 37.0 ⁇ 0.5°C and the rotating paddle speed was fixed at 75 rpm.
• Single dose units were poured in a container containing 50 mL of tap water. After 5 minutes, the suspension was poured in the dissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10 mL of water were used to rinse the container and were added to the dissolution vessel.
• Table 17f Time (hour) % dissolved 0 0 0,25 46 1 51 3 52 4 59 6 94 8 98 10 98 12 98 16 98
• Example 17c Mixture Eudragit TM L100-S100 (50-50)
• IR particles were prepared as follows: 1615.0g of Sodium Oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone - Plasdone TM K30 from ISP) were solubilized in 1903.2g of absolute ethyl alcohol and 1267.1g of water. The solution was entirely sprayed onto 300g of microcrystalline cellulose spheres (Cellets TM 127 from Pharmatrans) in a fluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 268 microns were obtained.
• the finished composition which contains a 50:50 mixture of MR and IR particles calculated on their sodium oxybate content, was prepared as follows: 223.0g of the above IR particles, 318.4g of the above MR coated particles, 11.2g of malic acid (D/L malic acid regular from Bartek), 4.0g of xanthan gum (Xantural TM 75 from CP Kelco), 6.0g of carragenan gum (Viscarin TM PH209 from FMC Biopolymer), 6.0g of hydroxyethylcellulose (Natrosol TM 250M from Ashland ) and 2.9g of magnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.14g (corresponding to a 4.5g dose with half of the dose as immediate-release fraction and half of the dose as modified release fraction) were weighed.
• Figure 80 and Table 17j depict dissolution profiles determined using a USP apparatus 2 in 0.1N HCl.
• the dissolution medium was maintained at 37.0 ⁇ 0.5°C and the rotating paddle speed was fixed at 75 rpm.
• Single dose units were poured in a container containing 50 mL of tap water. After 5 minutes, the suspension was poured in the dissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10 mL of water were used to rinse the container and were added to the dissolution vessel.
• Table 17j Time (hour) % dissolved 0 0 0,25 47 1 51 3 51 6 59 8 80 10 92 12 96 16 97
• Table 18c compares the pharmacokinetic parameters AUC inf and C 8h obtained for 4.5g of the test product to the same parameters calculated 2 x 2.25g, i.e. 4.5 g total dose of Xyrem ® .

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